Academic Commons Search Resultshttp://academiccommons.columbia.edu/catalog.rss?f%5Bdepartment_facet%5D%5B%5D=Urology&q=&rows=500&sort=record_creation_date+desc
Academic Commons Search Resultsen-usRole of promoter hypermethylation in Cisplatin treatment response of male germ cell tumorshttp://academiccommons.columbia.edu/catalog/ac:184516
Koul, Sanjay; McKiernan, James; Narayan, Gopeshwar; Houldsworth, Jane; Bacik, Jennifer; Dobrzynski, Deborah; Assaad, Adel; Mansukhani, Mahesh; Reuter, Victor; Bosl, George; Chaganti, Raju; Murty, Vandavallihttp://dx.doi.org/10.7916/D81V5CBWMon, 08 Sep 2014 00:00:00 +0000Male germ cell tumor (GCT) is a highly curable malignancy, which exhibits exquisite sensitivity to cisplatin treatment. The genetic pathway(s) that determine the chemotherapy sensitivity in GCT remain largely unknown. We studied epigenetic changes in relation to cisplatin response by examining promoter hypermethylation in a cohort of resistant and sensitive GCTs. Here, we show that promoter hypermethylation of RASSF1A and HIC1 genes is associated with resistance. The promoter hypermethylation and/or the down-regulated expression of MGMT is seen in the majority of tumors. We hypothesize that these epigenetic alterations affecting MGMT play a major role in the exquisite sensitivity to cisplatin, characteristic of GCTs. We also demonstrate that cisplatin treatment induce de novo promoter hypermethylation in vivo. In addition, we show that the acquired cisplatin resistance in vitro alters the expression of specific genes and the highly resistant cells fail to reactivate gene expression after treatment to demethylating and histone deacetylase inhibiting agents. Our findings suggest that promoter hypermethylation of RASSF1A and HIC1 genes play a role in resistance of GCT, while the transcriptional inactivation of MGMT by epigenetic alterations confer exquisite sensitivity to cisplatin. These results also implicate defects in epigenetic pathways that regulate gene transcription in cisplatin resistant GCT.Oncology, Molecular biologysk1276, jmm23, mm322Urology, Irving Comprehensive Cancer Center, Pathology and Cell BiologyArticlesHuman sex hormone-binding globulin gene expression- multiple promoters and complex alternative splicinghttp://academiccommons.columbia.edu/catalog/ac:185012
Nakhla, Atif; Hryb, Daniel; Rosner, William; Romas, Nicholas A.; Xiang, Zhaoying; Kahn, Scott M.http://dx.doi.org/10.7916/D8J964TSMon, 08 Sep 2014 00:00:00 +0000Human sex hormone-binding globulin (SHBG) regulates free sex steroid concentrations in plasma and modulates rapid, membrane based steroid signaling. SHBG is encoded by an eight exon-long transcript whose expression is regulated by a downstream promoter (PL). The SHBG gene was previously shown to express a second major transcript of unknown function, derived from an upstream promoter (PT), and two minor transcripts. We report that transcriptional expression of the human SHBG gene is far more complex than previously described. PL and PT direct the expression of at least six independent transcripts each, resulting from alternative splicing of exons 4, 5, 6, and/or 7. We mapped two transcriptional start sites downstream of PL and PT, and present evidence for a third SHBG gene promoter (PN) within the neighboring FXR2 gene; PN regulates the expression of at least seven independent SHBG gene transcripts, each possessing a novel, 164-nt first exon (1N). Transcriptional expression patterns were generated for human prostate, breast, testis, liver, and brain, and the LNCaP, MCF-7, and HepG2 cell lines. Each expresses the SHBG transcript, albeit in varying abundance. Alternative splicing was more pronounced in the cancer cell lines. PL- PT- and PN-derived transcripts were most abundant in liver, testis, and prostate, respectively. Initial findings reveal the existence of a smaller immunoreactive SHBG species in LNCaP, MCF-7, and HepG2 cells. These results extend our understanding of human SHBG gene transcription, and raise new and important questions regarding the role of novel alternatively spliced transcripts, their function in hormonally responsive tissues including the breast and prostate, and the role that aberrant SHBG gene expression may play in cancer.Medicinewr7, nar1, smk1Urology, MedicineArticlesA Retrotransposon Insertion in the 59 Regulatory Domain of Ptf1a Results in Ectopic Gene Expression and Multiple Congenital Defects in Danforth’s Short Tail Mousehttp://academiccommons.columbia.edu/catalog/ac:163173
Lugani, Francesca; Arora, Ripla; Papeta, Natalia F.; Patel, Ami M.; Zheng, Zongyu; Sterken, Roel; Singer, Ruth Arielah; Caridi, Gianluca; Mendelsohn, Cathy Lee; Sussel, Lori; Papaioannou, Virginia E.; Gharavi, Ali G.http://hdl.handle.net/10022/AC:P:21043Fri, 12 Jul 2013 00:00:00 +0000Danforth's short tail mutant (Sd) mouse, first described in 1930, is a classic spontaneous mutant exhibiting defects of the axial skeleton, hindgut, and urogenital system. We used meiotic mapping in 1,497 segregants to localize the mutation to a 42.8-kb intergenic segment on chromosome 2. Resequencing of this region identified an 8.5-kb early retrotransposon (ETn) insertion within the highly conserved regulatory sequences upstream of Pancreas Specific Transcription Factor, 1a (Ptf1a). This mutation resulted in up to tenfold increased expression of Ptf1a as compared to wild-type embryos at E9.5 but no detectable changes in the expression levels of other neighboring genes. At E9.5, Sd mutants exhibit ectopic Ptf1a expression in embryonic progenitors of every organ that will manifest a developmental defect: the notochord, the hindgut, and the mesonephric ducts. Moreover, at E 8.5, Sd mutant mice exhibit ectopic Ptf1a expression in the lateral plate mesoderm, tail bud mesenchyme, and in the notochord, preceding the onset of visible defects such as notochord degeneration. The Sd heterozygote phenotype was not ameliorated by Ptf1a haploinsufficiency, further suggesting that the developmental defects result from ectopic expression of Ptf1a. These data identify disruption of the spatio-temporal pattern of Ptf1a expression as the unifying mechanism underlying the multiple congenital defects in Danforth's short tail mouse. This striking example of an enhancer mutation resulting in profound developmental defects suggests that disruption of conserved regulatory elements may also contribute to human malformation syndromes.Genetics, Developmental biology, Medicinefl2233, ra2219, np2192, amp2202, zz2104, rs2964, ras2217, clm20, lgs2, vep1, ag2239Urology, Medicine, Cellular, Molecular and Biomedical Studies, Genetics and DevelopmentArticlesAndrogen Receptor-Target Genes in African American Prostate Cancer Disparitieshttp://academiccommons.columbia.edu/catalog/ac:163100
Wang, Bi-Dar; Yang, Qi; Ceniccola, Kristin; Bianco, Fernando J.; Andrawis, Ramez; Jarrett, Thomas; Frazier, Harold; Patierno, Steven R.; Lee, Norman H.http://hdl.handle.net/10022/AC:P:21020Thu, 11 Jul 2013 00:00:00 +0000The incidence and mortality rates of prostate cancer (PCa) are higher in African American (AA) compared to Caucasian American (CA) men. To elucidate the molecular mechanisms underlying PCa disparities, we employed an integrative approach combining gene expression profiling and pathway and promoter analyses to investigate differential transcriptomes and deregulated signaling pathways in AA versus CA cancers. A comparison of AA and CA PCa specimens identified 1,188 differentially expressed genes. Interestingly, these transcriptional differences were overrepresented in signaling pathways that converged on the androgen receptor (AR), suggesting that the AR may be a unifying oncogenic theme in AA PCa. Gene promoter analysis revealed that 382 out of 1,188 genes contained cis-acting AR-binding sequences. Chromatin immunoprecipitation confirmed STAT1, RHOA, ITGB5, MAPKAPK2, CSNK2A,1 and PIK3CB genes as novel AR targets in PCa disparities. Moreover, functional screens revealed that androgen-stimulated AR binding and upregulation of RHOA, ITGB5, and PIK3CB genes were associated with increased invasive activity of AA PCa cells, as siRNA-mediated knockdown of each gene caused a loss of androgen-stimulated invasion. In summation, our findings demonstrate that transcriptional changes have preferentially occurred in multiple signaling pathways converging (“transcriptional convergence”) on AR signaling, thereby contributing to AR-target gene activation and PCa aggressiveness in AAs.Oncology, Genetics, Medicinefb2271UrologyArticlesRoles in Retinoid Signaling in the Lower Urinary Tracthttp://academiccommons.columbia.edu/catalog/ac:148241
Gandhi, Devanginihttp://hdl.handle.net/10022/AC:P:13569Thu, 21 Jun 2012 00:00:00 +0000Retinoic acid (RA)-signaling is involved in a broad spectrum of cellular processes, including formation of most embryonic tissues, epithelial differentiation, and is a critical regulator of stem cell differentiation in vitro. Studies from our lab have focused on the role of RA-signaling in the urinary tract, where we find that it plays multiple roles. By inducing expression of a floxed dominant-negative mutant Rar receptor, termed RaraDN, in the bladder, we find that RA-receptor signaling from the bladder epithelium plays distinct roles during urinary tract development; it is required for establishing mature ureter-bladder connections and for differentiation of the bladder epithelia. Congenital abnormalities of the kidney and urinary tract (CAKUT) characterize a range of lower urinary tract defects such as kidney and ureter agenesis, hydronephrosis, and vesicoureteral reflux. Development of the lower urinary tract, which consists of the kidneys, ureters, bladder, and urethra, is crucial for removal of toxic substances from the blood and depends on patent connections between the ureter and the bladder. Impaired vitamin A signaling, either by maternal vitamin A deficiency in mice, or deleting RA-synthesizing enzymes and RA-receptors, leads to syndromic urinary tract abnormalities similar to those seen in humans. Our previous studies have suggested that proper ureter-bladder connections depend on signals derived from the bladder. By selectively inhibiting RA-signaling in the bladder epithelium, we show that RA-receptor signaling from the bladder is required for nephric duct (ND) insertion into the cloacal epithelium, CND maturation, and late-stage ureteral apoptosis in part through Ret. In addition, we find that RA acts independently of Ret where it regulates bladder growth and epithelial differentiation. The bladder epithelium, or urothelium, is a stratified epithelium that lines the major portion of the lower urinary tract and provides a crucial barrier between urine and blood. It contains basal, intermediate, and umbrella cells that synthesize and traffic uroplakin proteins to its apical surface. Vitamin A has been shown to be necessary for preventing keratinization of the bladder epithelia, and in vitro, it can induce the differentiation of endodermal ES cells into populations of cells that express markers of the urothelium. Recent studies suggest that Shh-expressing population in the adult bladder contains progenitors that can repopulate the urothelium after damage. Here we report that RA-receptor-dependent signaling temporally regulates Shh-expressing urothelial progenitors and is required for formation of intermediate and umbrella cells during early development. Furthermore, we find that in the absence of RA-signaling, Shh-progenitors undergo a fate change, down-regulating uroplakins and up-regulating squamous markers, suggesting that RA is normally required for either positively regulating urothelial differentiation or negatively suppressing squamous differentiation.Genetics, Developmental biology, Nutritiondvg2101Urology, Institute of Human Nutrition, Nutritional and Metabolic Biology, Genetics and Development, Pathology and Cell BiologyDissertationsExamining the Role and Regulation of Cell-Cell Adhesion in Aggressive Prostate Cancerhttp://academiccommons.columbia.edu/catalog/ac:131480
Barber, Alison G.http://hdl.handle.net/10022/AC:P:10251Fri, 29 Apr 2011 00:00:00 +0000Prostate cancer is the second leading cause of cancer death in American men, yet despite the prevalence of this disease, there is a distinct lack of prognostic biomarkers for estimating the likelihood of prostate cancer aggressiveness. The loss of cell-cell adhesion is frequently associated with the progression of prostate cancer to a metastatic state. While both adherens junctions and desmosomes are involved in establishing and maintaining this adhesion, previous studies of cell-cell adhesion in prostate cancer have focused solely on the role of adherens junctions, leaving the role of desmosomal adhesion unexplored. The goals of this thesis were to perform a functional analysis of the role and regulation of adherens junctions and desmosomes in aggressive prostate cancer, and to examine the efficacy of classical and desmosomal cadherins as prognostic biomarkers of aggressive prostate cancer. I began this study by characterizing the expression profile of desmosomal cadherins in normal human prostate and metastatic prostate cancer cell lines. This study revealed that DSG2, DSC2, and DSG4 were consistently expressed at a high level in the luminal cells of the prostate. Further, analysis of metastatic prostate cancer cell lines showed that the expression of DSG2 is present in most cell lines examined, while the expression of DSG4 is absent. Following this characterization, I examined the role of E-cadherin and DSG2 in metastatic prostate cancer cell lines. Interestingly, the loss of E-cadherin resulted in the inhibition of extensive primary and metastatic tumor formation, suggesting that E-cadherin may have a role in promoting the progression of prostate cancer in addition to its well-established role as a tumor suppressor. Additionally, the loss of E-cadherin based adherens junctions was not associated with the reciprocal loss of DSG2 based desmosomes, challenging the common belief that the formation of adherens junctions is a prerequisite for the formation of desmosomes. I then examined the regulatory effects of PI3K/AKT signaling on E-cadherin and DSG2 expression in metastatic prostate cancer cell lines. The expression of activated AKT was found to be associated with the inhibition of E-cadherin expression, while the expression of DSG2 was relatively unperturbed in the presence of activated AKT expression. These results suggest that aberrantly activated PI3K/AKT signaling in prostate cancer may result in the loss of E-cadherin expression, and that the loss of E-cadherin and DSG2 expression in prostate cancer may be regulated by separate pathways. Finally, I examined the expression of E-cadherin and DSG2 in a large cohort of patients with prostate cancer to determine whether these cadherins were associated with prostate cancer aggressiveness. Interestingly, the loss of these cadherins was found to be significantly associated with biochemical recurrence demonstrating their potential utility as prognostic markers of aggressive prostate cancer.Genetics, Developmental biologyaeg2103Urology, Genetics and Development, Pathology and Cell BiologyDissertations